4 Oct 2021 Episode 179 More on origin, standardization of neut assays, need and effects of booster, a novel Chinese S protein vaccine and a novel immunotherapy.

Dear colleagues,

A mixed episode with follow-up in various areas, related to vaccination.  But we start with the ongoing debate on origin and we end with a potential novel immunotherapy.    

More on origin

Ep 179-1: is a short summary of a very interesting debate, organized by Jon Cohen (Science), between 4 prominent scientist, 2 American (Michael Worobey and Jesse Bloom) and 2 of Chinese origin (Linfa Wang and Alina Chan), who provide a balanced view on whether the virus originated “naturally” (via the trade in live animals in the “wet” market in Wuhan) or passed via the Wuhan Institute of Virology, where the virus could have been “modified” (especially in the so-called “furin cleavage site”) and an (accidental) “lab leak” may have happened.   Those who are interested in the details should spend an interesting hour listening to the actual debate, during which I was sometimes more convinced of the “natural” hypothesis and at other times I inclined to the “lab leak”.  At the end, I wouldn’t dare to express a firm opinion on the matter…. 

However, in my view, the most important key concept during the debate was “(lack of) transparency”.  Obviously, if I was a virologist in Wuhan, I would not be pleased by the many wild accusations that have been launched over the last 1.5 year in all kinds of media and by offensive people like Donald Trump, but if there is nothing to hide in this famous institution, why not open all databases and lab notes to WHO investigators and show that indeed this is a world class research institution, where such things do not happen?   Noblesse oblige.

Follow the live debate at https://www.science.org/content/article/lab-leak-and-natural-origin-proponents-face-civilly-forum-pandemic-origins?utm_campaign=news_daily_2021-09-30&et_rid=17279631&et_cid=3940584

Standardization and validation of neutralization assays

Ep 179-2: A peer-reviewed study, comparing various assays was published in J Clin Microbiol.  Using 40 convalescent plasma, the authors demonstrate that 50 % and 80% neut titers in cell-based assays, using either live (recombinant) virus or (non-replicative) pseudoviruses are strongly correlated amongst each other (mostly >  0.80 see Fig 2 p. 10).  The correlation with the more convenient “surrogate” neutralization assay, that measures the antibody-mediated inhibition of binding between recombinant spike and ACE-2 receptor, is somewhat weaker (same Fig 2) and this assay is also less sensitive (Fig 1 p. 7).  Moreover the correlation between live virus neut and ELISA for spike- or receptor-binding (RBD) antibodies is also > 0.80 (bottom line in Fig 2), while the correlation of these binding antibodies with the pseudovirus and surrogate assays is somewhat weaker.

Clearly, as nicely summarized in Table 2 p. 9, the live virus assay is most demanding (biosafety level 3 and labor-intensive), the pseudovirus assays are in between (level 2) and the surrogate assay is the easiest and less-demanding.     

Ep 179-3: An earlier study on a larger convalescent plasma panel (> 330) in  J Virol Meth also showed a good correlation between the conventional neut assay (with unmodified live virus), the surrogate assay and the binding antibodies and confirms a lower sensitivity for the surrogate assay.

Obviously, the limitation of both standardization exercises is that only plasma from convalescent patients were used and that there is no correlation with protection.

Ep 179-4: offers such “validation” in a medRxiv preprint (24 Sept).  It is based on live SARS-CoV-2 variants neutralising antibody titres from individuals, vaccinated with the Pfizer BNT162b2 mRNA vaccine against various VOC (see Fig 2 p. 6) on one hand and the results of phase 3 trials and real world observations in various countries.  It is one of these huge British modeling exercises, which shows that the effectiveness, predicted from the neut assay corresponds closely with the really observed effectiveness (Fig 5 p. 9). 

Ep 179-5: Comparison of immune responses in established vaccines, using the same assays.  This study confirms that Pfizer and Moderna vaccines elicit higher neutralizing titers than Janssen. Moderna induced the highest T cell responses (IFN-g ELISPOT after Spike peptide stimulation).

Reviews on vaccine effectiveness against variants:

Ep 179-6: A systematic review and meta-analysis, including randomized trials, cohorts and case-control studies confirms that full vaccination effectiveness against COVID by VOC of mRNA vaccines are superior to Adeno and inactivated vaccines:

• Alpha: RNA= 91 % >  Protein = 86 % > Adeno = 74 %
• Beta: RNA = 80 % > Protein = 51 % > Adeno = 45 %
• Delta RNA = 76 % > Adeno = 64 % > inactivated = 62.5 %

Clearly, the definition of vaccine effectiveness is not standardized and there were many other “confounding factors”, which differed in these studies (such as age, background risk of infection, duration of observation etc.). Nevertheless, the overall picture is consistent with what we gradually learned over the last year….

Ep 179-7: A more interesting British modeling, based on cohort data, estimating the “infectivity” of index cases and “susceptibility to infection” in contacts.

1. Summary of Table (p. 21): Odd’s ratio of PCR(+) in contacts according to vaccination status of index or contact: comparing unvaccinated with full vaccination of either index or contact with regard to alpha and delta variant

• Stronger reduction after Pfizer than Astra-Zeneca
• Stronger reduction of contact susceptibility than index infectivity
• Weaker effect of vaccination on Delta as compared to Alpha variant

2. Fig 1 p. 23:  clear weaning of protection against transmission in function of time, especially for index, delta and Astra-Zeneca: after 8 weeks an index vaccinated with AZ becomes as infectious as a non-vaccinated index.

Remarkably, viral load was not a dominant factor!

These data are only about infection, not disease

Nevertheless, provide arguments for booster, especially  after AZ, to prevent onwards transmission.

Reviews on response to vaccination in immunocompromised patients

Ep 179-8: Meta-analysis by Ryan in medRxiv, using clear selection criteria (including control group and serological titers p. 5).  After 2 doses with any of the “Western” vaccines (mRNA or Adeno) + Chinese CoronaVac (inactivated): percentage of seroconversion in

Healthy control = 99 % > solid cancers 92 > immune-mediated inflammatory disorders (rheumatoid arthritis etc) 79 > hematological cancers 68 > organ transplant recipients 29. 

Clear need for booster in these populations.  Two examples in transplant patients are given:

• Ep 179-8 A: 3rd Moderna two months after 2nd: 55 % additional seroconversion vs 18 % in control. See figure for favorable data on neut and T cell responses.
• Ep 179-8 B: 3rd Pfizer increased seroconversion from 41 to 67 %. Not surprisingly, younger patients seroconverted more and those receiving more immunosuppressive drugs seroconverted less.

Ep 179-9: Meta-analysis on effect of anti-CD20 (B cell depletion) therapy: overall 41 % serconversion (and 71 % T cell response) rate after 2 doses: Determining factors:

• Time since last anti-CD20 (as could be expected): < 6 months = 20 %; > 6 months = 63 %
• Type of indication: seroconversion = 43 % for auto-immune disease; 39 % for cancer and only 14 % for organ transplant indications (reflecting Ep 179-8).  

A small study (Ep 179-9 A) also shows benefit for a booster in this population.

Ep 179-10: Again some good news for people living with HIV: a comparison of longer-term response to the Astra-Zeneca (ChAd Ox1) vaccine in a cohort of HIV (+) 54 subjects, with undetectable viral load and CD4+ T counts > 350, but also clearly raised activation/exhaustion markers (Fig 1 p. 33-, as compared to matched HIV(-) controls: the curves of antibody  responses to RBD (Fig 2 D p. 34) and T cell Elispot (Fig 3 B p. 35) are very similar up to 6 months after vaccination!

Booster in immunocompetent subjects

Ep 179-11: Laurence Chu on Oct 1 in medRxiv: clearly favorable effect of 3rd Moderna after 6 months:

• Similar reactogenicity
• Around 2 fold higher neutralization titers against D614G and Delta variant 1 month after 3rd dose as compared to 1 month after 2nd dose.

Ep 179-12: Patamatamkul from Thailand on Sept 28 in medRxiv: clearly favorable effect of either Pfizer or Astra-Zeneca as booster in CoronaVac vaccinated health care workers.  It is not very clear what the exact time interval was between second CoronaVac and booster. Nevertheless it is evident that:

• Anti-RBD titers rise dramatically after booster by either vaccine (Fig 1 A p. 9)
• Surrogate neutralization after CoronaVac was rather weak and raised dramatically after both types of booster (Fig 1 B p. 9 and Fig 2)
• The response to Pfizer is higher than AZ
• Quite some reactogenicity to both boosters.

In both studies there is no reference to age-dependent differences in the effect of 3rd dose.

Ep 179-13:  A recent article in Eos magazine, a popular science journal in Dutch on the 3rd jab (de derde prik).  Just as a background and potential didactic material for reaching out to a general public.

A novel S protein-based Chinese vaccine

Ep 179-14: A nice series of slides, released on 22 Sept by Clover Co.  The vaccine is described on slide 2 as SCB-2019 antigen (30 μg/dose) in combination with CpG 1018 adjuvant and aluminum hydroxide (alum), to be administered twice IM over 3 wks.  This antigen is a recombinant SARS-CoV-2 Spike (S) protein, preserved in the native trimeric prefusion conformation form by Trimer-TagTM. 

According to the presented results, this vaccine is 100 % effective against hospitalization and protects against COVID of any severity 91.8 % for gamma VOC; 78.7 % for delta and 58.6 % Mu (slide 17).  Remarkably, efficacy against any COVID was only 55 % for other strains combined (alpha, beta, lambda, theta and others), without any details on subdivision.

There was no difference in efficacy according to age or comorbidities (slide 18) and the protection in subjects, previously infected with SARS-CoV-2, was in the same range as the uninfected (slide 19), although the former had higher titers of neutralizing Ab induced (slide 23). Favorable safety profile (slide 20-21). Clearly, this vaccine seems more active than the previous Chinese vaccines (the inactivated and the Ad5)

The SCB-2019 antigen seems very similar to NVX-CoV237, from Novavax, which is formulated with “saponin-based” Matrix M adjuvant, but is used at 6 X lower dose (5 µg) also twice IM.  According to the official report on phase 3 in NEJM (Ep 179-14 B) the efficacy of Novavax against COVID of any severity was about 90 % in UK, when the alpha virus was circulating.  The efficacy against beta in South-Africa was only around 50 % in a phase 2 a-b study (Ep 179-14 C).   Ep 179-14-D is a recent overview in Cell, with slightly different figures.  

Therefore, it is possible that Novavax is slightly less effective than Clover, maybe because of the lower dosing or the different adjuvant used?

Ep 179-15: provides a health-economic context of this new Chinese vaccine that certainly reinforces China’s position as the major provider of vaccines to low and middle income countries via bilateral agreements and via the WHO COVAX program.  

A potential novel immunotherapy, based on anti-CD73

Ep 179-16:  A preprint in medRxiv of 28 Sept describes the effects of this Ab (mupadolimab), with a presumed double action:

• Blocking the ecto-enzyme CD73, thus preventing the conversion of AMP into immunosuppressive Adenine.
• Activating  B cells, promoting their differentiation and immunoglobulin class switching.

After a reassuring dose-escalating phase 1, a phase 3 was initiated in mild to moderate hospitalized patients, but it was terminated mid-2021, due to waning COVID in the US(?) The rather premature results in a small number (summarized in Table 3 p. 27) show a favorable effect (clinical improvement). 

Obviously, this result needs confirmation.  I just mention this study, because it is a very novel concept.

SOME GENERAL CONCLUSIONS    

1. The debate on the natural versus lab leak origin continues.  It could be resolved, if the Chinese authorities opened up the databases and lab notes of the Wuhan Institute to an independent international panel. Why not?

2. Standardization and validation of neutralization assays is ongoing.  There is also an interesting WHO document in this regard https://www.who.int/news-room/feature-stories/detail/standardization-of-vaccines-for-coronavirus-disease-covid-19

3. Various meta-analysis and modeling exercises confirm that mRNA vaccines are superior to Adeno vectors, the protein-based Novavax and the inactivated vaccines, both in terms of efficacy against COVID and in terms of transmission prevention. 

4. Meta-analyses also confirms that patients with organ transplant or hematological cancers are not well responding to COVID vaccines.  Increasing age and immunosuppressive therapies (especially B cell depleting anti-CD20) are unfavorable.    

5. Boosters with mRNA or Adenoviral vectors raise the neutralizing antibodies dramatically, both in healthy and immunosuppressed subjects.

6. There is an interesting  novel Chinese S protein vaccine (SCB-2019  from Clover co.)  that is at least as good or better than NVX-CoV237 (Novavax), with efficacy against variants very close to mRNA vaccines .  One of the advantages of these protein-based vaccines is that they do not need to be frozen, but are stable in a regular fridge.

7. Very preliminary positive results of COVID immunotherapy with anti-CD73.

Best wishes,

Guido